Centre for Cardiovascular Biology and Medicine, Department of Medicine, The Rayne Building, University College London, 5 University Street, London WC1E 6JJ, UK.
Br J Cancer. 2010 Feb 2;102(3):541-52. doi: 10.1038/sj.bjc.6605539. Epub 2010 Jan 19.
Neuropilin-1 (NRP1) is a non-tyrosine kinase receptor for vascular endothelial growth factor (VEGF) recently implicated in tumour functions.
In this study we used a specific antagonist of VEGF binding to the NRP1 b1 domain, EG3287, to investigate the functional roles of NRP1 in human carcinoma cell lines, non-small-cell lung A549, kidney ACHN, and prostate DU145 cells expressing NRP1, and the underlying mechanisms involved.
EG3287 potently displaced the specific binding of VEGF to NRP1 in carcinoma cell lines and significantly inhibited the migration of A549 and ACHN cells. Neuropilin-1 downregulation by siRNA also decreased cell migration. EG3287 reduced the adhesion of A549 and ACHN cells to extracellular matrix (ECM), and enhanced the anti-adhesive effects of a beta1-integrin function-blocking antibody. EG3287 increased the cytotoxic effects of the chemotherapeutic agents 5-FU, paclitaxel, or cisplatin on A549 and DU145 cells, through inhibition of integrin-dependent cell interaction with the ECM.
These findings indicate that NRP1 is important for tumour cell migration and adhesion, and that NRP1 antagonism enhances chemosensitivity, at least in part, by interfering with integrin-dependent survival pathways. A major implication of this study is that therapeutic strategies targeting NRP1 in tumour cells may be particularly useful in combination with other drugs for combating tumour survival, growth, and metastatic spread independently of an antiangiogenic effect of blocking NRP1.
神经纤毛蛋白-1（NRP1）是一种非酪氨酸激酶受体，可与血管内皮生长因子（VEGF）结合，最近被认为与肿瘤功能有关。
在这项研究中，我们使用了一种特异性的 VEGF 结合 NRP1 b1 结构域的拮抗剂 EG3287，来研究 NRP1 在表达 NRP1 的人癌细胞系（非小细胞肺癌 A549、肾 ACHN 和前列腺 DU145）中的功能作用及其潜在机制。
EG3287 可有效置换 VEGF 与癌细胞系中 NRP1 的特异性结合，并显著抑制 A549 和 ACHN 细胞的迁移。NRP1 的 siRNA 下调也降低了细胞迁移。EG3287 降低了 A549 和 ACHN 细胞与细胞外基质（ECM）的黏附，并增强了β1 整联蛋白功能阻断抗体的抗黏附作用。EG3287 通过抑制整合素依赖的细胞与 ECM 的相互作用，增强了化疗药物 5-FU、紫杉醇或顺铂对 A549 和 DU145 细胞的细胞毒性作用。
这些发现表明，NRP1 对肿瘤细胞的迁移和黏附很重要，NRP1 拮抗作用通过干扰整合素依赖的存活途径，至少部分增强了化疗敏感性。这项研究的一个主要意义是，针对肿瘤细胞 NRP1 的治疗策略可能与其他药物联合使用特别有用，可独立于阻断 NRP1 的抗血管生成作用来抵抗肿瘤的存活、生长和转移扩散。
